Those compounds are inhibitors of group IV phosphodiesterases and, for that reason, have especially valuable therapeutic applications.
The functions of most organic tissues are modulated by endogenous substances (hormones, neurotransmitters, autacoids) or by exogenous substances. For some of those substances, the biological effect is relayed at intracellular level by enzyme effectors, such as adenylate cyclase or guanylate cyclase. Stimulation of the enzymes that are responsible for the synthesis of cyclic nucleotides, such as cyclic adenosine-3',5'-monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP), causes an increase in the intracellular level of those second messengers involved in regulating numerous biological functions (E. W. SUTHERLAND and W. RALL, Pharmacol. Rev., Vol. 12, p. 265, 1960). Breakdown of the cyclic nucleotides is effected by a family of enzymes, called phosphodiesterases (PDE), currently classified in 7 groups. The recognition of different isoforms within each of those groups, and of the tissue-specific or cell-specific distribution of certain isoforms, has stimulated research into increasingly specific inhibitors of individual types of isoenzyme (J. A. BEAVO, Physiological Rev., Vol. 75, no. 4, pp. 725-749, 1995). Of the various PDE families, PDE IV has been identified in a large number of tissues or cells, such as brain, heart, vascular endothelium, vascular and tracheobronchial smooth muscle and haematopoietic cells. Inhibition of the phosphodiesterases slows down the hydrolysis of the cyclic nucleotides and brings about an increase in cAMP and/or cGMP level.
PDE IV inhibitors, which are responsible for an increase in cAMP levels, have anti-inflammatory activities and relaxant effects on tracheobronchial smooth muscle, hence their therapeutic value in the field of respiratory pathology and pathologies associated with an inflammatory process (M. N. PALFREYMAN, Drugs of the Future, Vol. 20, no. 8, pp. 793-804, 1995; J. P. BARNES, Eur. Respir. J., Vol. 8, pp. 457-462, 1995; S. B. CHRISTENSEN and T. J. TORPHY, Annual Reports in Medicinal Chemistry, Vol. 29, pp. 185-194, 1994, Academic Press).
Those compounds which are inhibitors of group IV phosphodiesterases will be especially valuable in therapeutic applications concerned with inflammation and bronchial relaxation and more precisely in asthma and chronic obstructive bronchopathies (A. J. DUPLANTIER and J. B. CHENG, Annu. Rep. Med. Chem., Vol. 29, p. 73-81, 1994), (C. D. NICHOLSON and M. SHAHID, Pulmonary Pharmacol., Vol. 7, p. 1-17, 1994), (T. J. TORPHY, G. P. LIVI and S. B. CHRISTENSEN, Drug News Perspect., Vol. 6, p. 03-214, 1993), (J. A. LOWE and J. B. CHENG, Drugs Future, Vol. 17, p. 799-807, 1992), but also in all disorders such as rhinites (I. RADERER, E. HAEN, C. SCHUDT and B. PRZYBILLA, Vienna. Med. Wochenschr., Vol. 145, p. 456-8, 1995), acute respiratory distress syndrome (ARDS) (C. R. TURNER, K. M. ESSER and E. B. WHEELDON, Circulatory Shock, Vol. 39, p. 237-45, 1993), allergies and dermatites (J. M. HANIFIN and S. C. CHAN, J. Invest. Dermatol., Vol. 105, p. 84S-88S, 1995), (J. M. HANIFIN, J. Dermatol. Sci., Vol. 1, p. 1-6, 1990), psoriasis (E. TOUITOU, N. SHACO-EZRA, N. DAYAN, M. JUSHYNSKI, R. RAFAELOFF and R. AZOURY, J. Pharm. Sci., Vol. 81, p. 131-4, 1992), (F. LEVI-SCHAFFER and E. TOUITOU, Skin Pharmacol., Vol. 4, p. 286-90, 1991), rheumatoid arthritis (J. M. ANAYA and L. R. ESPINOZA, J. Rheumatol., Vol. 22, p. 595-9, 1995), autoimmune diseases, (C. P. GENAIN et al. Proc. Natl. Acad. Sci., Vol. 92, p. 3601-5, 1995), multiple sclerosis (N. SOMMER et al., Nat. Med., Vol. 1, p. 244-8, 1995), dyskinesias (T. KITATANI, S. HAYASHI and T. SAKAGUCHI, Nippon. Yakurigaku. Zasshi, Vol. 86, p. 353-8, 1985), glomerulonephritis (M. HECHT, M. MULLER, M. L. LOHMANN-MATTHES and A. EMMENDORFFER, J. Leukoc. Biol., Vol. 57, p. 242-249, 1995), osteoarthritis and septic shock (A. M. BADGER, D. L. OLIVERA and K. M. ESSER Circ. Shock, Vol. 44, p. 188-195, 1994; L. SEKUT et al., Clin. Exp. Inmunol., Vol. 100, p. 126-132, 1995), AIDS (T. F. GRETEN, S. ENDRES et al., AIDS, Vol. 9, p. 1137-1144, 1995), depression (N. A. SACCOMANO et al., J. Med. Chem., Vol. 34, p.291-298, 1991), and any neurodcgenerative disease that is accompanied by inflammatory symptoms, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Down's syndrome and amyotrophic lateral sclerosis (G. Z. FEUERSTEIN et al., Ann. N. Y. Acad. Sci., Vol. 765, p. 62-71, 1995).
Those therapeutic indications are not limiting inasmuch as a decrease in cellular cAMP concentration, whatever the cause and tissue location, results in cellular malfunction, giving rise to pathological symptoms, and may constitute an important therapeutic target for the products described.